Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

PURPOSE: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. METHODS: In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. RESULTS: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). CONCLUSION: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

[Tricky cases in in-vitro diagnostics of hymenoptera venom allergy]. / Problemfälle der In-vitro-Diagnostik bei Hymenopterengiftallergie.

BACKGROUND: Hymenoptera stings give rise to anaphylactic reactions in 1.2-3.5 % of the population. The risk of repeat anaphylaxis following subsequent stings is greatly reduced through immunotherapy with the culprit venom. A prerequisite for allergen-specific immunotherapy is a precise diagnostic work-up. AIMS AND OBJECTIVES: We review the efficacy of currently available in-vitro diagnostic tests for hymenoptera venom allergy in different clinical scenarios. METHODS: A targeted literature review in PubMed and a review of the current guideline on hymenoptera venom allergy were performed. For illustrative purposes, a series of clinical cases from our allergy department are presented. RESULTS AND CONCLUSION: The correct diagnosis in hymenoptera venom allergy is influenced by a number of factors including patients' ability to identify the insect and time lapsed to diagnostic tests. The high rate of clinically irrelevant sensitizations, cross-reactivity and suboptimal sensitivity of the currently available diagnostic tests further complicate the picture. In the case of multiple sensitizations, molecular allergy diagnostics has improved the detection of clinically relevant sensitizations allowing the cost and risks of unnecessary double immunotherapy to be avoided. This is true in particular with regard to wasp venom allergy. For bee venom allergy, improvements in molecular allergy diagnostics have shown promising results and their implementation in clinical practice is planned. In patients with no sensitization in skin or serological tests but with a convincing history of insect sting anaphylaxis, the increased sensitivity of a basophil activation test may deliver crucial evidence of venom sensitization. The value of the basophil activation test may be further improved using specific marker allergens. The diagnosis of allergy to paper wasps (Polistinae) and white-faced hornets (Dolichovespula) remains problematic as they show partial cross-reactivity to wasp venom and specific marker allergens particular to these, still have to be identified.